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Precocious Puberty

Basics

Description

- GDPP (4) - Caused either by a central dysregulation of the hypothalamic-pituitary-gonadal axis resulting in overproduction of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) or by ectopic hormone production such as hCG by a neoplasm - Characterized by pubertal levels of FSH and LH - Affected individuals have advanced bone age and short stature due to premature epiphyseal closure. - Different causes include the following: - Idiopathic central precocious puberty is the most common type. - CNS lesions such as glioma, astrocytoma, hypothalamic hamartoma, and arachnoid cysts - Congenital CNS anomaly such as hydrocephalus - Infection such as encephalitis and meningitis - Trauma - CNS irradiation - Primary hypothyroidism - Gain-of-function mutation of the GPR54 protein, which is part of an essential signaling complex for the initiation of puberty

- Boys - Germ cell tumors secreting hCG - Leydig cell tumors - Familial male-limited precocious puberty or testotoxicosis caused by an activation mutation of the LH-receptor gene

  • Defined as the appearance of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys
  • Normal puberty occurs between age 8 and 14 years in girls and 9 and 14 years in boys (1,2).
  • There are three types:Gonadotropin-dependent precocious puberty (GDPP) or central precocious puberty. Manifests secondary sexual characteristics in harmony such as bilateral breasts or testicular enlargementGonadotropin-independent precocious puberty (GIPP) or peripheral precocious puberty. Does not manifest secondary sexual characteristics in harmony. It presents a clinical picture of incomplete puberty.Incomplete precocious puberty such as premature, adrenarche, and thelarche

Epidemiology

  • More prevalent in African American children compared to White children
  • Attention to racial differences is advised because African American girls normally develop secondary sexual characteristics at an earlier age than White girls.
  • It is 10 times more common in girls than in boys.
  • 80 " 90% of affected girls have idiopathic central precocious puberty (1,3).

Incidence

Estimated incidence of 0.01 " 0.05% per year in the United States (1)

Prevalence

In a population-based Danish study from 1993 to 2001, it was found that 0.2% of Danish girls and <0.05% of Danish boys were affected by some type of precocious puberty (3).

Etiology and Pathophysiology

  • GDPP (4)Caused either by a central dysregulation of the hypothalamic-pituitary-gonadal axis resulting in overproduction of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) or by ectopic hormone production such as hCG by a neoplasmCharacterized by pubertal levels of FSH and LHAffected individuals have advanced bone age and short stature due to premature epiphyseal closure.Different causes include the following:Idiopathic central precocious puberty is the most common type.CNS lesions such as glioma, astrocytoma, hypothalamic hamartoma, and arachnoid cystsCongenital CNS anomaly such as hydrocephalusInfection such as encephalitis and meningitisTraumaCNS irradiationPrimary hypothyroidismGain-of-function mutation of the GPR54 protein, which is part of an essential signaling complex for the initiation of puberty
  • GIPP (1)[B]Caused by excess secretion of androgens or estrogens produced from the gonads or adrenal glands or from exogenous sourcesFSH and LH levels are in the prepubertal range.Causes include the following:GirlsOvarian tumors such as Leydig cell tumors or granulosa cell tumorsOvarian cystBoysGerm cell tumors secreting hCGLeydig cell tumorsFamilial male-limited precocious puberty or testotoxicosis caused by an activation mutation of the LH-receptor geneBoth boys and girlsAdrenal androgen production due to adrenocorticotropic hormone (ACTH) stimulation: congenital adrenal hyperplasia, 21-hydroxylase deficiency, 11- ²-hydroxylase deficiencyMcCune-Albright syndrome: a triad of precocious puberty, cafe-au-lait skin pigmentation, and fibrous dysplasia of the boneExcess exogenous estrogen exposure from creams, sprays, or ointments
  • Incomplete precocious puberty (1)A variant of normal pubertyPresents with early development of secondary sexual characteristics
  • Premature thelarcheCan occur in two peaks: during the first 2 years of life and between ages 6 and 8 yearsMore common in Black and Hispanic children14 " 20% of children affected can develop true precocious puberty.Characterized byDevelopment of isolated unilateral or bilateral breastsAbsence of other sexual characteristicsNormal linear growth and normal bone ageSex hormones level are in the prepubertal range.
  • Premature adrenarcheCharacterized by the appearance of pubic and/or axillary hair, acne, and adult body odor before the age of 8 years in girls and 9 years in boysNormal linear growth and bone ageCommon in girls and individuals with insulin resistance and obesity20% of girls affected can develop polycystic ovarian syndrome as adults.Most cases are idiopathic but may be caused by congenital adrenal hyperplasia, 21-hydroxylase deficiency, Cushing disease, dehydroepiandrosterone-sulfate (DHEA-S) deficiency, autonomous endogenous or exogenous excess.

General Prevention

Precocious puberty is not preventable, but early detection is helpful, so the following steps are recommended:

  • Careful growth chart review
  • Thorough physical exam for early signs of puberty
  • Anticipatory guidance in late childhood should include normal pubertal development.

Diagnosis

Any child with secondary sexual characteristics before the age of 8 years in girls and before the age of 9 years in boys should be evaluated (4)[B].

History

  • Review past medical history, social history, and onset of puberty in family members.
  • Review features of puberty present, rate of progression, and duration.
  • Review growth charts for linear growth velocity.
  • Presence of exogenous sources of sex steroids in the home

Physical Exam

  • Measurement of height, weight, and height velocity (cm/year)
  • Funduscopic exam and visual acuity test for possible CNS mass effect
  • Complete neurologic exam to assess for CNS pathology
  • Skin exam for cafe-au-lait spots (McCune-Albright syndrome)
  • Tanner stage breasts and pubic hair in girls
  • Measure testicular volume and penile size (3).

Differential Diagnosis

  • Benign gynecomastia of adolescence
  • CNS and pituitary lesions
  • Exogenous sex hormones
  • Adrenal hyperplasia
  • Polycystic ovarian syndrome
  • Ovarian tumor
  • Adrenal tumor
  • Cushing syndrome

Diagnostic Tests & Interpretation

Initial Tests (lab, imaging)

  • Assess bone age of any child who presents with early secondary sexual characteristics (2)[A]. Accelerated bone age present in GDPP and GIPP but not in incomplete precocious puberty.
  • Measure basal LH level and FSH level after gonadotropin-releasing hormone (GnRH) administration, which will differentiate between GDDP and GIPP.GDPP: LH and FSH levels are at pubertal levels, which will increase with administration of GnRH (1)[B],(2)[A]. Additional testing once the diagnosis of GDDP is made might include estradiol, testosterone, thyroid function tests, and MRI of the brain for identifiable CNS causes.GIPP: LH and FSH are at prepubertal range and will not respond to GnRH agonist. Additional testing to identify peripheral causes might include testosterone, estradiol, LH, FSH, dehydroepiandrosterone (DHEA), DHEA-S, 17-hydroxyprogresterone, hCG (in boys), and abdominal and pelvic ultrasound in girls for evaluation of ovarian cyst or tumor. Testicular ultrasound in boys to evaluate for possible Leydig cell tumorPremature thelarche: Normal levels of gonadotropins and estradiol, unremarkable pelvic ultrasoundPremature adrenarche: Prepubertal range LH and FSH and will not respond to GnRH agonist.

Treatment

General Measures

  • GDPP: The primary reason to treat is to prevent early epiphyseal closure and reduction of adult height.
  • Good candidates are those who present at a younger age with rapidly progressing skeletal age compared to height age.
  • Recommended to follow progression for 3 " 6 months in children who present with slow progression of puberty and height velocity before considering treatment (1)[B].
  • Final height may increase 8 " 12 cm.

Medication

First Line

  • GDPP: GnRH agonists such as leuprolide or triptorelin are the drugs of choice (5)[A],(6)[B].Treatment can be discontinued by age 11 years in girls and age 12 years in boys.Puberty returns on average 16 months after discontinuation of GnRH agonist.
  • GIPP: Treat underlying conditions. It does not respond to GnRH agonists (1)[B].
  • Incomplete precocious puberty: No therapy is required, but children should be monitored closely and reassurance should be given to patient and family (1)[B].

Issues for Referral

  • Refer to endocrinologist for management of GDDP.
  • Refer to neurologist for underlying intracranial processes.

Ongoing Care

Follow-up Recommendations

GDPP

  • Evaluate every 3 " 6 months to assess pubertal growth and development and height velocity to detect abnormal growth spurt (1)[B].
  • Measure bone age every 6 " 12 months with x-ray of epiphyseal growth plate of the hand.
  • May also measure LH and sex steroids 2 months after the start of therapy or after changing dose, which should be in the prepubertal levels
  • Adequate treatment should stop breast, testicular, phallus, and pubic hair development and should slow rate of height velocity and bone age maturation.

Prognosis

  • Treatment reduces height velocity and children may achieve predicted height.
  • May reduce psychosocial stressors associated with precocious puberty

Complications

  • Short stature
  • Psychosocial stressors associated with early onset of puberty

References

1.Chauhan A, Grissom M. Disorders of childhood growth and development: precocious puberty. FP Essent. 2013;410:25 " 31.

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2.Huffman GB. Reassessing the age limit of precocious puberty in girls. Am Fam Physician. 2000;61(6):1850 " 1852.3.Teilmann G, Pedersen CB, Jensen TK, et al. Prevalence and incidence of precocious pubertal development in Denmark: an epidemiologic study based on national registries. Pediatrics. 2005;116(6):1323 " 1328.

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4.Papadimitriou A, Beri D, Tsialla A, et al. Early growth acceleration in girls with idiopathic precocious puberty. J Pediatr. 2006;149(1):43 " 46.

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5.Lee PA, Klein K, Mauras N, et al. 36-month treatment experience of two doses of leuprolide acetate 3-month depot for children with central precocious puberty. J Clin Endocrinol Metab. 2014;99(9):3153 " 3159.

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6.Bertelloni S, Baroncelli GI. Current pharmacotherapy of central precocious puberty by GnRH analogs: certainties and uncertainties. Expert Opin Pharmacother. 2013;14(12):1627 " 1639.

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Codes

ICD09

  • 259.1 Precocious sexual development and puberty, not elsewhere classified
  • 253.1 Other and unspecified anterior pituitary hyperfunction

ICD10

  • E30.1 Precocious puberty
  • E22.8 Other hyperfunction of pituitary gland

SNOMED

  • 400179000 Precocious puberty (disorder)
  • 237816004 Central precocious puberty (disorder)
  • 19911007 Precocious female puberty (disorder)
  • 190291004 Premature puberty due to hypothyroidism (disorder)

Clinical Pearls

  • There are three types of precocious puberty: central, peripheral, and incomplete.
  • Most common in girls and majority of cases represent idiopathic central precocious puberty
  • GnRH agonists are the mainstay treatments for central precocious puberty; young individuals with rapidly progressing skeletal age will benefit the most.